The active site of the HCV protease domain is extremely hydrophobic, flat, and solvent-exposed, with few pockets to increase the affinity for an inhibitor to bind. Given the chemical nature of the substrate-binding site, it is not surprising that no suitable HTS leads were identified. Peptide inhibitor truncation studies revealed that the affinity for binding was spread over a wide area. To increase the interaction of a small molecule with the protease active site, Robert Perni and co-workers introduced a covalent, reversible electrophilic alpha-ketoamide �warhead� into the inhibitor design to increase the half-life of binding to the protease. The increased half-life had a surprising and significant impact when the biological properties non-covalent and covalent HCV protease inhibitors were compared. Interestingly, both of the first HCV protease inhibitors (telaprevir, INCIVEK; boceprevir, VICTRELIS) approved for use in combination with pegylated interferon alfa-2a and ribavirin are covalent ketoamide inhibitors.

Discovery and development of telaprevir- a covalent HCV protease inhibitor recently approved for the treatment of people with chronic genotype 1 HCV infection

245th National Meeting (2013)

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